Updates in SJS/TEN: collaboration, innovation, and community.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination.

BACKGROUND: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. METHODS: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status. RESULTS: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. CONCLUSION: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Is This Medication Safe for My Child? How to Discuss Safety of Commonly Used Medications With Parents.

All drugs have potential side effects, but thoughtful use can maximize benefits while minimizing risks. Children should not be considered just small adults regarding drug safety because their growth and development are discordant with their ability to sense and self-report drug side effects. Detecting side effects requires vigilance and education from prescribers to parents, who are tasked with monitoring their child over time. A drug's safety profile is published in the package label after pivotal trials are conducted in relatively small and sometimes narrow segments of the population during the U.S. Food and Drug Administration approval process. Drug safety profiles can change as data from postmarketing reports and long-term monitoring during phase IV trials emerge. As such, prescribers are obligated to maintain current understanding of any changes to drug labels. Discussing potential side effects, monitoring, and when to report concerns can be a time-consuming process during patient encounters. This review offers current information regarding potential side effects of some of the most commonly used medications for allergic conditions, asthma, and atopic dermatitis. This information and discussion will hopefully assist clinicians in their conversations with parents, including advice surrounding prescribing medication to minimize adverse effects, parental monitoring, and documentation.

Feasibility of a Centralized, Pharmacy-Led Penicillin Allergy Delabeling Program.

BACKGROUND: Penicillin allergy labels are often inaccurate in children and removing unnecessary labels results in improved outcomes and lower health care costs. Although the hospital setting is a frequent point of contact for children, strategies to evaluate penicillin allergies in the hospital are lacking. METHODS: We performed a prospective pilot study to determine the feasibility of a centralized, pharmacy-led approach to penicillin allergy evaluation. Children with a reported history of penicillin allergy admitted to our children's hospital were risk-stratified and those stratified as low-risk underwent a single-dose oral challenge by a central pharmacist, regardless of the need for antibiotics. After the completion of each patient's delabeling process, surveys were distributed to health care personnel involved in the patient's care to collect perceptions on the acceptability, appropriateness, and feasibility of this intervention. Measures were scored by using a 5-point Likert scale. RESULTS: Of the 23 patients who screened as low-risk, 20 underwent a penicillin allergy evaluation and an oral challenge. Of these, the penicillin allergy label was removed in 19 (95%) patients (Fig 1). The median age was 7 years (range 11 months-18 years). Participants rated the risk stratification and delabeling favorably overall, with high ratings on all 3 implementation measures: acceptability (mean 4.55, ± standard deviation [STD] 0.65), appropriateness (mean 4.58, STD ± 0.6), and feasibility (mean 4.51, STD ± 0.73). Measures of acceptability, appropriateness, and feasibility remained high when stratified by health care worker type and provider type. CONCLUSIONS: Our findings provide support for systemic implementation of penicillin allergy delabeling strategies in hospitalized children.

Rapid progress in our understanding of COVID-19 vaccine allergy: A cause for optimism, not hesitancy.

Anaphylaxis is a life-threatening condition and when associated with vaccination, leads to vaccine hesitancy. The concerns around vaccine-related anaphylaxis have become even more important during the coronavirus disease 2019 (COVID-19) pandemic where the COVID-19 vaccines remain one of our most important tools. Although rates of anaphylaxis to COVID-19 vaccines are not significantly different from those to other vaccines, Centers for Disease Control and Prevention guidance recommends avoidance of the same COVID-19 vaccine in individuals who had an allergic reaction or are allergic to a COVID-19 vaccine component. Fortunately, our understanding of COVID-19 vaccine allergic reactions has improved dramatically in the past year in large part due to important research efforts from individuals in the allergy community. Initially, researchers published algorithmic approaches using risk stratification and excipient skin testing. However, as our experience and knowledge improved with ongoing research, we have better data showing safety of repeat vaccination despite an initial reaction. We review our progress starting in December 2020 when the Food and Drug Administration approved the first COVID-19 vaccine in the United States through early 2022, highlighting our success in understanding COVID-19 vaccine reactions.

Immediate and Delayed Hypersensitivity Reactions to Beta-Lactam Antibiotics.

Beta-lactam antibiotics are the most commonly reported drug allergy in adults and children. More than 95% of those with reported allergy labels to beta lactams are not confirmed when subjected to allergy testing. Beta lactam antibiotics are associated with a wide spectrum of immediate and delayed drug hypersensitivity reactions. The latency period to symptoms and clinical presentation aids in the causality assessment. Risk stratification based on diagnosis and timing then allows for appropriate management and evaluation. Skin prick testing, intradermal testing and oral challenge are well established for evaluation of immediate reactions. Delayed intradermal testing, patch testing and oral challenge can also be considered for evaluation of mild to moderate delayed reactions. Cross-reactivity between beta-lactams appears to be driven most commonly by a shared R1 side-chain. Standardized algorithms, protocols and pathways are needed for widespread implementation of a pragmatic and effective approach to patients reporting beta lactam allergy.

Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines.

Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti-polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.

Children with reported penicillin allergy: Public health impact and safety of delabeling.

OBJECTIVE: To review the relevant literature related to children with reported penicillin allergy and highlight the different ways in which children could be delabeled and to evaluate the public health impact that a penicillin allergy has for children. DATA SOURCES: Data for this review were obtained via PubMed searches and then retrieval of articles from their respective journals for further review. STUDY SELECTIONS: Studies regarding the safety of different ways to evaluate penicillin allergy in children were identified via PubMed searches. Any study that reported different ways of testing (3-tier, direct oral challenge, 5-day oral challenges) were included. This same format was used when selecting relevant articg:les related to the costs, prescription patterns, and stewardship trends associated with a penicillin allergy label. RESULTS: This review found that penicillin allergy testing is a safe and effective way to delabel those with reported allergy. In children with low-risk allergy symptoms, a direct oral challenge approach may be optimal. In those children with a history of high-risk allergy symptoms, a 3-tiered approach is ideal. The review also found that there is a significant cost associated with reported penicillin allergy and that there are increased negative health benefits to those children with reported allergy. CONCLUSION: Penicillin allergy is overdiagnosed, often incorrectly, and the label is frequently first applied during childhood. Targeting children for the removal of the incorrect penicillin allergy label provides a mechanism to reduce the use of broader-spectrum and less effective antibiotics.

Pediatric Drug Hypersensitivity.

PURPOSE OF REVIEW: Pediatric drug hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric drug hypersensitivity and highlight new developments in diagnosis and management. RECENT FINDINGS: This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for ß-lactam reactions. We review unique aspects of pediatric drug challenges and desensitizations. It is important to accurately diagnose pediatric drug hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient's treatment. Utilization of weight-based dose and infusion rate adjustments for current drug challenge and desensitization protocols optimize success.

Drug allergy in children and adults: Is it the double X chromosome?

OBJECTIVE: This article reviews the latest science and epidemiologic studies related to drug allergy in children and adults to explore possible mechanisms related to female propensity for drug allergy. DATA SOURCES: PubMed literature review, focusing primarily on the last 5 years. STUDY SELECTIONS: Articles reviewing the science behind female predisposition to atopic and asthmatic conditions and epidemiologic studies reviewing drug allergy and drug-induced anaphylaxis. RESULTS: Despite adult female predilection for atopic conditions, few laboratory studies explore sex-specific mechanisms in atopic/allergic diseases, and most are focused on autoimmunity and asthma. Drug allergy is more frequently reported in adult females compared with adult males. Adult females are also more likely to have drug-induced anaphylaxis (DIA), although no clear sex predominance has been reported in fatal or severe DIA. Studies in children suggest the reverse picture, with prepubertal males more likely to have drug allergy and DIA than prepubertal girls. CONCLUSION: Possible explanations for female predisposition for drug allergy are multifactorial and include disproportionate utilization of health care with more exposure to antibiotics or medications, genetic factors related to the X chromosome, epigenetic changes, and discrepant hormonal interactions with immune cells.

Antibiotic Allergy in Pediatrics.

The overlabeling of pediatric antibiotic allergy represents a huge burden in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug-virus interaction, and they usually do not represent a long-lasting, drug-specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins.

Management of Children with Hypersensitivity to Antibiotics and Monoclonal Antibodies.

Proper management of drug allergy in children is based on a thorough history, in vitro testing (if available), in vivo testing, and drug challenge. This approach has been well developed with beta-lactam drugs but not with non-beta-lactam drugs and monoclonal antibodies. Children commonly develop rashes during an antibiotic course, which can lead to misdiagnosis of drug allergy. Clinical reactions to monoclonal antibodies vary and are managed depending on the type. A better knowledge of drug reactions that can occur in antibiotic allergy and monoclonal allergy can aid a provider in better management of their drug-allergic pediatric patients.